The present lack of blood-based diagnosis requires AD patients to be subjected to either invasive spinal fluid (CSF) tapping, expensive MRI or PET imaging, or arduous psychological testing, all unsuitable and costly for our elderly. Strategically, we shall address this unmet need by generating systemic biomarkers detectable in peripheral mononuclear cells (PBMC) and serum/plasma, focusing on two classes of molecules, micro- RNAs and their target genes, which generally exhibit an inverse relationship because the former noncoding RNA functions by partially repressing the latters expression as a dimmer switch, via binding either at the co- ding region of the message, thus degrading it, or at the 3-untranslated region, to inhibit translation. Thus, key microRNAs and their targets can serve as disease biomarkers, in see-saw balance, applicable for new diagnostics and/or therapy. Our pilot study with a small cohort of 16 AD and 16 age-matched normal elderly controls (NEC) revealed: 1. Predominant down-regulation of gene expression at the message level in AD PBMC; and 2. Correlated up-regulation of microRNA (miR) expression in PBMC of the same individuals. In this proposal, we focus on a specific up-regulated microRNA, miR-34a, whose known targets are SIRT1, cdk4, cdk6, cyclin E2, bcl2, etc. SIRT1 is a member of the 7-member Silent Information Regulator protein family. Caloric restriction extends longevity through triggering expression of SIRT1, which can also be mimicked by resveratrol, a red wine polyphenol. SIRT1 reduction is linked to accumulation of Tau and A242 production, two hallmarks of AD etiopathogenesis. Thus, we suggest that in AD there is a systemic effect detectable in PBMC and serum/plasma; up-regulated miR-34a may induce down-regulation of SIRT1, with attendant pathophysiologic results. In this proposal, we plan to generate for this see-saw of changes miR-34a/SIRT1 Target Pair Ratio (TPR) indices, to quantify both disease presence as well as progress; the indices should also provide an unprecedented evaluation of drug efficacy. This Fast-track proposal of two phases is planned with our existing small cohort study as the roadmap for the larger cohort investigation: Phase I of six months with our existing small 16 AD and 16 NEC sample cohorts to: Aim 1. study possible down-regulation of miR-34as known targets; and Aim 2. develop a feasibility study of pilot miR-34a/SIRT1 TPR-indices; and Phase II of two years with larger cohorts of 200 AD and 200 NEC participants: Aim 1.Establish a Bio-Repository of PBMC-DNA, -RNA & -protein specimens, and serum/plasma samples for assays in Aims 2 & 3; Aim 2. Generate PBMC-based miR34a/SIRT1 (& other targets) TPR indices; and Aim 3. Perform feasibility study to develop serum/plasma-based miR- 34a/SIRT1-TPR indices. Success of this project will allow us to generate PBMC- and serum-based miR-TPR indices as personalized diagnostics for AD victims, meeting an urgent need in health care, a huge gain for disease victims, their caregivers, and our society at large. PUBLIC HEALTH RELEVANCE: At present, the absence of any blood-based diagnosis for Alzheimers disease (AD) requires patients to enduring arduous neuropsychological testing, invasive cerebrospinal fluid tapping, and/or expensive MRI or PET imaging, with definitive diagnosis deferred until brain autopsy. Our preliminary findings, based on new science concerning a novel molecular species, microRNAs (miR) and their see-saw partial repression of the expression of their target gene(s), suggest that potential disease biomarkers for AD are detectable systemical- ly in peripheral blood mononuclear cells and/or serum/plasma, and may be quantified as miR-Target Pair Ra- tios (TPR). Our plan is to define AD-specific TPR indices, initially focusing on miR-34a and its target, SIRT1, whose reduction is known to be associated with increased Tau and A242, two hallmarks of AD etiopathogene- sis; our ultimate goal is a Tool-Box of TPR indices, miR-34a/SIRT1-TPR being the first such AD diagnostic, indicating not only disease presence, but also its progress (and even drug efficacy monitoring), a huge strate- gic gain for the victims of this costly disease, and our society at large!